Medical devices containing high inherent viscosity poly(p-dioxanone)

ABSTRACT

The present invention discloses polymers of poly(p-dioxanone having an inherent viscosity in the range of from 2.3 dL/g to about 8 dL/g, as determined at a concentration of 0.1 g/dL in hexafluoroisopropanol at 25° C. This invention also describes improved surgical devices and filaments made from poly(p-dioxanone) with an inherent viscosity in the range of from 2.3 dL/g to about 8 dL/g, determined at a concentration of 0.1 g/dL in hexafluoroisopropanol at 25° C. Additionally, disclosed are processes for manufacturing poly(p-dioxanone) with an inherent viscosity in the range of from 2.3 dL/g to about 8 dL/g, as determined at a concentration of 0.1 g/dL in hexafluoroisopropanol at 25° C., as well as, processes for molding surgical articles and extruding surgical filaments from these polymers.

This is a continuation, of application Ser. No. 08/270,712, filed Jul.5, 1994, now U.S. Pat. No. 5,611,986.

FIELD OF THE INVENTION

This invention relates to high inherent viscosity polymers ofp-dioxanone. More specifically this invention relates to high inherentviscosity polymers of p-dioxanone which are suitable for melt processinginto surgical devices and filaments that have improved mechanicalproperties and in vivo survival rates.

DESCRIPTION OF THE PRIOR ART

Polymers of p-dioxanone were first reported by Schultz et al. in U.S.Pat. Nos. 3,063,967 and 3,063,968. Schultz describes makingpoly(p-dioxanone) with intrinsic viscosities of from 1.98 to 2.83 dL/g,determined at 25° C. using a Ubbelohde viscometer at a concentration of0.5 g per 100 cc of tetrachloroethane using zinc, mercury and cadmiumbased catalysts. Originally Schultz proposed using these polymers forcoatings and textile fibers. However, poly(p-dioxanone) is not suitablefor use as a general textile fiber or coating because the polymer ishighly susceptible to hydrolysis.

Doddi et al. was the first to recognize that the susceptibility ofpoly(p-dioxanone) to hydrolysis provided a unique utility forpoly(p-dioxanone). In U.S. Pat. No. 4,052,988 Doddi described the use ofpoly(p-dioxanone) in bioabsorbable medical devices such as surgicalsutures, pins, screws and. reinforcing plates. subsequently, medicaldevices and a process for molding medical devices such as staples andclips from poly(p-dioxanone) were described in U.S. Pat. Nos. 4,490,326and 4,620,541. The poly(p-dioxanone) polymer used in these inventionsgenerally had an inherent viscosity in the range of from about 1.2 dL/gto about 2.26 dL/g.

Commercially available sutures and suture clips manufactured frompoly(p-dioxanone) are made from polymers that have an inherent viscosityin the range of from about 1.6 to about 1.92 dL/g. Polymer with inherentviscosities within this range were convenient to extrude and mold intomedical devices because the melt viscosity of these polymers were lowenough for conventional extrusion and injection molding. Polymers withhigher inherent viscosities were not used because the polymers were verydifficult to manufacture and process. Additionally, there was no reasonto believe that the incremental improvement in polymer properties wouldbe sufficient to warrant going to higher inherent viscosity polymers.For example, in molding, since the zero shear melt viscosity ofpoly(p-dioxanone) polymers increases by approximately the fifth power ofthe inherent viscosity, high inherent viscosity polymers often requireworking at higher pressures with more expensive molding machinery.

The only other method for making a poly(p-dioxanone) medical device withan inherent viscosity of greater than 2.26 dL/g is disclosed by Hinschet al. in EPA 274 898. Hinsch describes a method for producing an opencell foam by first polymerizing p-dioxanone at a temperature of fromabout 120° to 150° C. then adding solvents to the polymer, freeze dryingthe resulting mixture to form the foam and remove excess unreactedmonomer. However, the process for making poly(p-dioxanone) described inHinsch produces an open cell porous foam material which is unsuitablefor melt processing into filaments or medical devices.

As discussed above, the prior art processes for manufacturingpoly(p-dioxanone) generally produce polymeric material that has aninherent viscosity under 2.26 dL/g or that is unsuitable for surgicaldevices. The process described by Schultz uses catalysts that are notapproved for medical grades of poly(p-dioxanone), therefore, Schultz'sprocess is not suitable for use in surgical devices. The processdisclosed by Doddi produces a poly(p-dioxanone) which is suitable formaking surgical devices; however, Doddi did not describe making polymerswith an inherent viscosity above 2.26 dL/g. The process disclosed byHinsch although providing a high molecular weight poly(p-dioxanone)polymer does not produce a material which may be readily incorporatedinto melt processed surgical devices because of the air entrained in theopen cell foam. Additionally, making a poly(p-dioxanone) polymer with aninherent viscosity above 2.26 dL/g is very difficult. The monomer musthave a high and consistent purity, and the initiator added to beginpolymerization must be precisely determined to assure obtaining thedesired molecular weight of poly(p-dioxanone). Therefore, an alternateprocess needs to be employed to manufacture high inherent viscositypoly(p-dioxanone).

Surprisingly, we have discovered a high inherent viscositypoly(p-dioxanone) that can be melt processed into medical device such assuture clips, sutures and plates, that have significantly improvedproperties such as longer in vivo survival surgical articles, as wellas, greater strength and toughness.

SUMMARY OF THE INVENTION

The present invention provides a polymer of poly(p-dioxanone) suitablefor use in surgical devices and surgical filaments having an inherentviscosity of from 2.3 dL/g to about 8 dL/g tested at 25° C. at aconcentration of 0.1 g/dL in hexafluoroisopropanol with a bulk densityof from about 1.3 g/cc to about 1.45 g/cc and a monomer content of lessthan 5 percent by weight.

In an additional embodiment of the present invention there is provided amedical device comprising a melt processed device of poly(p-dioxanone)wherein the inherent viscosity of the poly(p-dioxanone) is in the rangeof from 2.3 dL/g to about 8 dL/g, tested at 25° C. at a concentration of0.1 g/dL in hexafluoroisopropanol and a bulk density of from about 1.3g/cc to about 1.45 g/cc.

In another embodiment of the present invention there is provided animproved surgical filament comprising a filament of poly(p-dioxanone)having an inherent viscosity in the range of from 2.3 dL/g to about 3.5dL/g tested at 25° C. at a concentration of 0.1 g/dL inhexafluoroisopropanol.

In a further embodiment of the present invention there is provided adeformable surgical article comprising a surgical article containingpoly(p-dioxanone) having an inherent viscosity in the range of fromabout 2.10 dL/g to about 3.5 dL/g tested at 25° C. at a concentration of0.1 g/dL in hexafluoroisopropanol.

In yet another embodiment of the present invention there is provided aprocess for making a high inherent viscosity poly(p-dioxanone) polymercomprising determining the amount of water, free acid and reactiveimpurities in a lot of monomer containing at least 80 mole percentp-dioxanone, the balance of the monomer being a lactone monomer selectedfrom the group consisting of glycolide, lactide, ε-caprolactone andtrimethylene carbonate; polymerizing the lot of monomers in a suitablereaction vessel under suitable conditions for polymerizing the monomerin the presence of an organo-tin catalyst with a polymerizationinitiator provided in an amount sufficient after taking into account thepresence of the water, free acid and reactive impurities in the lot ofmonomer to provide a poly(p-dioxanone) containing polymer with aninherent viscosity of greater than 2.3 dL/g.

In yet a further embodiment of the present invention there is provided aprocess for manufacturing a surgical filament comprising extruding afilament containing poly(p-dioxanone) with an inherent viscosity in therange of from 2.3 dL/g to about 3.5 dL/g at a temperature of in therange of from about 135° C. to about 165° C. to form a filament; thenquenching said filament; then drawing said filament to form an orientedfilament.

In yet an additional embodiment of the present invention there isprovided a process for producing molded surgical devices from highinherent viscosity poly(p-dioxanone) comprising heatingpoly(p-dioxanone) with an inherent viscosity in the range of from 2.1dL/g to about 3.5 dL/g to a temperature in the range of from about 105°C. to about 140° C. to melt the poly(p-dioxanone); then injecting saidmelted poly(p-dioxanone) at a volumetric flow of greater than 0.7 cubicinches per second into a mold being maintained at a temperature above35° C.; cooling said melted poly(p-dioxanone) sufficiently to maintainits shape while in the mold; and removing said hardenedpoly(p-dioxanone) from the mold.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 graphically illustrates the yield strain values obtained fromfour poly(p-dioxanone) test articles versus the inherent viscosities ofthe polymers from which the test articles were molded. Three of the fourtest articles were annealed under an inert atmosphere for eight (8)hours at the indicated temperatures. The fourth test article was notannealed (raw).

FIG. 2 graphically illustrates the yield strain obtained from fourpoly(p-dioxanone) test articles versus the inherent viscosity of thepolymers contained in the test articles after they were molded. Three ofthe four test articles were annealed under an inert atmosphere for eight(8) hours at the indicated temperatures. The fourth test article was notannealed (raw).

FIG. 3 graphically illustrates the yield strain toughness obtained fromfour poly(p-dioxanone) test articles versus the inherent viscosity ofthe polymers from which the test articles were molded. The yield straintoughness was calculated by multiplying the shear stress by the squareroot of the shear strain. Three of the four test articles were annealedunder an inert atmosphere for eight (8) hours at the temperaturesindicated. The fourth test article was not annealed (raw).

FIG. 4 graphically illustrates the yield strain toughness obtained fromfour poly(p-dioxanone) test articles versus the inherent viscosities ofthe polymers contained in the test articles after molding. The yieldstrain toughness was calculated by multiplying the shear stress by thesquare root of the shear strain. Three of the four test articles wereannealed under an inert atmosphere for eight (8) hours at thetemperatures indicated. The fourth test article was not annealed (raw).

FIG. 5 graphically illustrates the improved in vivo survival of articlesmolded from high inherent viscosity poly(p-dioxanone) compared to testarticles molded from poly(p-dioxanone) of a lower inherent viscosity.

FIG. 6 is a schematic flow diagram showing the various steps in themethod of molding high inherent viscosity poly(p-dioxanone).

DETAILED DESCRIPTION OF THE INVENTION

The use of poly(p-dioxanone) with a high molecular weight or highinherent viscosity results in increased strength for surgical filaments,increased toughness, and a prolonged in vivo survival for articles madefrom poly(p-dioxanone). For the purpose of this invention a highinherent viscosity (HIV) poly(p-dioxanone) has an inherent viscosity ofabout 2.10 dL/g or greater. To obtain a medical device with an inherentviscosity of about 2.10 dL/g or greater the initial resin's inherentviscosity prior to melt processing must be higher than 2.10 dL/g.Commonly during melt processing the polymer's inherent viscosity willdrop due to polymer degradation that occurs during melt processing.Therefore, the initial inherent viscosity of poly(p-dioxanone) should bein the range of from 2.30 dL/g to about 8 dL/g, preferably in the rangeof from 2.4 dL/g to about 8 dL/g, more preferably in the range of from3.25 dL/g to about 8 dL/g and optionally may be in the range of fromabout 4.6 dL/g to about 8 dL/g tested at 25° C. at a concentration of0.1 g/dL in hexafluoroisopropanol. Currently, it is preferred that theinherent viscosity of poly(p-dioxanone) as determined from the medicaldevice be in the range of from 2.10 dL/g to about 8 dL/g, preferably inthe range of from 2.3 dL/g to about 8 dL/g, more preferably in the rangeof from 2.4 dL/g to about 8 dL/g, even more preferably in the range offrom about 3.25 dL/g to about 8 dL/g and optionally may be in the rangeof from about 4.6 dL/g to about 8 dL/g tested at 25° C. at aconcentration of 0.1 g/dL in hexafluoroisopropanol. For surgicalfilaments it is specifically preferred that the inherent viscosity ofthe poly(p-dioxanone) as determined from the filament be in the range offrom about 2.3 dL/g to about 3.5 dL/g and preferably in the range offrom 2.4 dL/g to 3.5 dL/g. Hereafter, unless otherwise stated allviscosities were determined at 25° C. at a concentration of 0.1 g/dL inhexafluoroisopropanol.

For the purpose of this invention, high inherent viscositypoly(p-dioxanone) polymer shall also include copolymers ofpoly(p-dioxanone) which contain up to 20 mole percent of another lactonemonomer (such as lactide, glycolide, ε-caprolactone or trimethylenecarbonate). Although, currently the preferred polymer ispoly(p-dioxanone) homopolymer.

As shown in FIG. 1 there are significant changes in the properties ofpoly(p-dioxanone) with increasing inherent viscosity (molecular weight).The graph of yield strain versus inherent viscosity shows that highinherent viscosity poly(p-dioxanone) undergoes permanent deformation atmuch higher elongation values than articles molded frompoly(p-dioxanone) with an initial inherent viscosity of less than about2.1 dL/g, determined at 25° C. at a concentration of 0.1 g/dL inhexafluoroisopropanol. Molded articles of poly(p-dioxanone) withinherent viscosities of about 2.1 dL/g, determined after molding, alsohave significantly improved yield strain values. Thus, medical devicesmade with high inherent viscosity poly(p-dioxanone) will undergosignificantly more reversible deformation; that is they will stretch orelongate more before becoming permanently deformed. It is particularlydesirable in fashioning hinged surgical clips to have a high yieldstrain, thereby allowing a single size clip to deform and accommodate agreater range of diameters of surgical sutures. Thus, a surgeon insteadof having to select the specific clip for each size suture would be ableto use one clip for many sizes of suture. Additionally, having one sizeof suture clip that will accommodate several sizes of sutures would bothreduce hospital and factory costs associated with manufacturing andmaintaining clip inventories.

FIG. 3 further demonstrates the improved yield strain toughness ofmolded articles made from a poly(p-dioxanone) polymer with an initialinherent viscosity (determined before melt processing) of greater than2.1 dL/g. FIG. 4 shows similar yield strain toughness curves based onthe inherent viscosity of poly(p-dioxanone) after it has been meltprocessed into test articles. Molded articles of poly(p-dioxanone) withinherent viscosity of about 2.1 dL/g, determined after molding, alsohave improved yield strain toughness values. Materials with high yieldstrain toughness are particularly desirable for melt processing intosurgical articles such as surgical clips, pins, screws etc. Surgicalarticles made of materials with high yield strain toughness are able tobear higher loads without deforming. This, for instance, would allow asuture clip to generate a higher suture holding force.

FIG. 5 shows that surgical devices with hinges molded frompoly(p-dioxanone), with an inherent viscosity above about 2.07 dL/g,have surprisingly improved in vivo survival rates compared to articlesmolded with an inherent viscosity of 1.91 dL/g. FIG. 5 demonstrates thatas the inherent viscosity of the poly(p-dioxanone) used to manufacturesuture clips was increased, the in vivo survival rate of the sutureclips significantly improved. The in vivo survival of the suture clipswere determined by locking a suture in the clip, implanting the sutureclip in an animal and recovering the clip for evaluation fourteen daysafter implantation. If after the suture clip was recovered the latch wasstill closed and the hinge was not broken the clip was scored as intact.The percent survival was calculated by dividing the total number ofclips that survived by the total number of clips evaluated andmultiplying by 100 percent.

Similarly, significant improvements in surgical filament properties canalso be achieved by increasing the inherent viscosity of thepoly(p-dioxanone) polymer used to make filaments (from an inherentviscosity of about 1.72 dL/g to about 2.30 dL/g, determined at 25° C. ata concentration of 0.1 g/dL in hexafluoroisopropanol). As shown inExample IV the properties of a filament produced from apoly(p-dioxanone) polymer with a final inherent viscosity of about 2.3dL/g, in an unoptimized extrusion and drawing process, showed a 31.5percent improvement in straight tensile strength compared to fiberprepared from a polymer with an inherent viscosity of about 1.72 dL/g.The toughness of the filament, as defined by the tensile strengthmultiplied by the square root of the elongation to break, increased by45 percent. The elongation and knot strength of the filament each alsoincreased by about 20 percent.

To manufacture poly(p-dioxanone) with an inherent viscosity of 2.1 dL/gor above, the process employed must control the amount of chain growthinitiators present in the polymerization reaction. This might have beenpreviously accomplished by specifying that the monomer have a purity ofgreater than, for instance, 99.7% (excluding nonreactive diluents).However, it is extremely expensive to commercially produce monomer ofgreater than 99.7% purity. Additionally, because of the hydrophilicnature of this monomer, it is also difficult to avoid watercontamination of the monomer after purification. Although starting withhigh purity p-dioxanone monomer is necessary to producepoly(p-dioxanone) having high inherent viscosity (HIV), other factorsmust be taken into consideration to reproducibly manufacture HIVpoly(p-dioxanone).

The inherent viscosity of poly(p-dioxanone) is directly related to themolecular weight distribution of the polymer. The molecular weight ofpoly(p-dioxanone) is controlled in large measure by the number ofpolymer chains that are initiated during polymerization. Although theinventors do not wish to be limited by scientific theory, it is believedthat for every mole of molecular weight control agent present, anothermole of polymer chains is produced. Therefore, for a given batch size,the greater the number of chains that are initiated and thus formed, thelower the corresponding average molecular weight of the resultantpolymer. Accordingly, to control the reaction to producepoly(p-dioxanone) of a precise molecular weight or inherent viscosity,the amount of molecular weight control agent that is needed must beprecisely determined.

The amount of the molecular weight control agent employed ispredetermined using a relationship which includes both the quantity andthe purity of the p-dioxanone monomer. More specifically, a measure ofthe purity of the p-dioxanone monomer, "a monomer test of inherentviscosity", is performed in a separate p-dioxanone test polymerization.This monomer test of inherent viscosity reflects the free acid, waterand miscellaneous impurities still normally contained in highly purifiedp-dioxanone monomer. Using the procedure outlined in Example I or asimilar para-dioxanone monomer test, the inherent viscosities should bein the range of from about 2 dL/g to about 8 dL/g as determined at 25°C. at a concentration of 0.1 g/dL in hexafluoroisopropanol. Monomerswith this level of purity can be used to produce high inherent viscositypoly(p-dioxanone) polymers. A preferred range of p-dioxanone testinherent viscosities for production of the high polymers of thisinvention are between 2.1 dL/g and 4.8 dL/g and are most preferred to bein the range of 3.0 to 4.4 dL/g. as determined at 25° C. at aconcentration of 0.1 g/dL in hexafluoroisopropanol. Monomer lots thatgive low inherent viscosity values are unsuitable for producing highinherent viscosity polymer of the present invention.

Monomer purification may be accomplished by methods well known to thepracticing organic chemist. Recrystallization from a suitable solvent orby distillation are particularly useful methods.

Although the inventors do not wish to be limited by scientific theory,it is believed that the relationship between the overall monomer toall-molecular-weight-control-agents mole ratio (R_(o)) and the additivesand impurities that can affect molecular weight is as follows:

    1/R.sub.o =1/R.sub.mwca +1/R.sub.w +1/R.sub.fa +1/R.sub.m  (1)

where

R_(o) =Overall monomer to all-molecular-weight-control-agents (includingboth intentionally added molecular control agents and impurities) moleratio

R_(mwca) =monomer to intentionally-added-molecular-weight-control-agentmole ratio

R_(w) =monomer to water-contained-in-monomer mole ratio

R_(fa) =monomer to free-acid-contained-in-monomer mole ratio

R_(m) =monomer to reactive-miscellaneous-impurities mole ratio; refersto impurities generated via handling, etc.

A test polymerization for p-dioxanone monomer, in the absence ofintentionally added molecular weight control agents, in practical terms,combines the effects of free acid, water, miscellaneous impurities,material handling, etc. into one measurable number that is correlatableto a particular monomer batch's ability to polymerize to high molecularweight. Thus,

R_(iv) =a mole ratio defined by the moles of monomer divided by thecombined moles of free acid, water, miscellaneous reactive impurities,etc. and,

    1/R.sub.iv =1/R.sub.w +1/R.sub.fa +1/R.sub.m               (2)

Combining equations 1 and 2 gives:

    1/R.sub.o =1/R.sub.mwca +1/R.sub.iv

We have discovered empirically that poly(p-dioxanone) prepared under agiven set of conditions has a relationship of inherent viscosity (IV) tothe overall ratio of moles of molecular weight control agent of thefollowing form:

    IV=A*R.sub.o.sup.a                                         (3)

where

a and A are constants in the equation IV=A*R_(o) ^(a) The values of theconstants A and a will vary according to the polymerization conditions.

IV=inherent viscosity of poly(p-dioxanone) polymer and

Similarly, the inherent viscosity of the test polymerization is relatedto the moles of monomer per mole of combined impurities

    IV.sub.m =K*R.sub.iv.sup.k                                 (4)

rearranging to solve for R_(iv)

    R.sub.iv =B*IV.sub.m.sup.b                                 (5)

where b and B are constants of the equation R_(IV) =B*IV_(m) ^(b) inwhich

IV_(m) =inherent viscosity of the poly(p-dioxanone) test polymerization

Substituting, the relationship between poly(p-dioxanone) polymerproperties, molecular weight control agent and the inherent viscosity ofa p-dioxanone monomer test polymerization into Equation (5) provides:

    (A/IV).sup.(1/a) =1/R.sub.mwca +1/(B*IV.sub.m.sup.b)       (6)

The constants; a, A, b and B have been approximated to be as follows:

a=0.61-0.71

A=0.015-0.058

b=3.4-7.5

B=3.7-76

Using the test polymerization described in Example I the constants weredetermined to be a=0.66, A=0.03, b=4.8 and B=25.8. Inserting thesevalues into Equation (6) and solving for R_(mwca) provides:

    1/R.sub.mwca =0.005/IV.sup.1.51 -1/(25.8*IV.sub.m.sup.4.8) (7)

In terms of grams of dodecanol per kilogram of p-dioxanone monomer(DDf):

    DDF=9.19/IV.sup.1.51 -70.8/IV.sub.m.sup.4.8                (8)

The purity of the p-dioxanone monomer (as related to test inherentviscosity of the monomer) significantly affects the overall quantity ofmolecular weight control agent required to produce a high inherentviscosity polymer to within a relatively narrow IV range. Unless thepurity level and impurities in the monomer are exactly the same for allmonomer lots, without the correction for impurities one would not beable to reproducibly produce high inherent viscosity polymers. Thus,without correcting for monomer impurities, the inherent viscosity ofpoly(p-dioxanone) polymerized under the same conditions will varywidely.

The high molecular weight poly(p-dioxanone) polymer produced asdescribed above can be processed to have a monomer content of notgreater than 5 percent by weight and preferably not greater than 4percent by weight, which is suitable for melt processing into a surgicaldevice. One process which may be used to synthesize poly(p-dioxanone)comprises ring-opening polymerization of 2-oxo-1,4-dioxane orp-dioxanone in the presence of an initiator (such as dodecanol or othermono or di-functional alkanol), a catalyst (such as tin catalyst i.e. ,tin(II) caprylate or stannous octoate) at elevated temperaturepreferably in the range of from about 100° C. to about 150° C. in a dryinert atmosphere for about 2 to about 10 hours. It is currentlypreferred to perform the polymerization at a temperature in the range offrom about 100° C. to about 120° C. because this temperature rangeprovides an optimum balance between the reaction rate of thepolymerization and the residual monomer content in the final polymer.The polymer produced by this process may then be further processed toincrease conversion and/or to remove any unreacted monomer by vacuumdrying the polymer or extruding the polymer through a vented twin screwextruder under conditions suitable to remove the unreacted monomer inthe polymer. Those skilled in the art will readily be able to determinesuitable extrusion conditions.

Alternatively, high inherent viscosity poly(p-dioxanone) polymer may beproduced by charging a vessel with a catalyst (such as stannousoctoate), an initiator (such as dodecanol or similar mono ordi-functional alkanol) and heating the reaction vessel to a temperaturein the range of from about 90° to about 140° C. for in the range of fromabout 30 minutes to about 5 hours. The polymer recovered from thisreaction may then be allowed to complete its polymerization at a lowertemperature in a conveniently sized container under an inert dryatmosphere at a temperature in the range of from about 60° to about 100°C. for in the range of from about 2 to about 7 days preferably from 3 to5 days. Those skilled in the art will recognize that the reactionconditions can be optimized by varying time and temperatures. Longerreaction times allow reaction mass to more closely approximate theequilibrium monomer content for a given polymerizing temperature. Theresultant polymers can be further processed to reduce residual monomercontent by vacuum drying or similar processes. The polymers produced bythis process also should be stored under a vacuum or inert atmosphereuntil they are used.

As previously stated, p-dioxanone can be copolymerized with up to 20mole percent of another lactone monomer including but not limited to,glycolide, lactide, ε-caprolactone and trimethylene carbonate. Thecopolymerization can produce high inherent viscosity poly(p-dioxanone)by taking into account the monomer properties of the other lactonemonomer as well as the p-dioxanone monomer properties as described abovein Equation (1).

The polymers described above may be melt processed into surgical devicesincluding but not limited to surgical devices selected from the groupconsisting of films, membranes, tapes, cords, pins(i.e. orthopaedicpins, produced by extrusion, oreintrusion or machining), clamps, screws,plates (i.e. maxillary prosthesis, temporary cranial plates and thelike), clips (i.e. suture clips and ligating clips), staples, hooks,buttons, snaps, bone plugs, bone anchors, bone substitutes, cartilagesubstitutes, tubes, gauze, meshes, and filaments (i.e. monofilament,multifilament, bicomponent and heterologous braids, ligatures such assutures, artificial tendons and ligaments). Particularly useful devicesfashioned from the polymers described above include surgical clips whichhave a hinge component, such as those described in U.S. Pat. Nos.4,620,541 and 5,160,339 assigned to Ethicon, Inc. and the receivercomponent from two piece fasteners as described in U.S. Pat. Nos.4,805,617, 4,889,119 and 4,890,613 (all five patents are herebyincorporated by reference herein). Suitable methods of melt processingpoly(p-dioxanone) polymers into these surgical devices is well known inthe art. U.S. Pat. No. 4,052,988 (which is hereby incorporated byreference) describes one suitable method for melt extruding, orientingand annealing the fiber to form sutures. Similarly, U.S. Pat. No.4,490,326 (which is hereby incorporated by reference) describes a moldeddevice and a process for molding and annealing molded devices ofpoly(p-dioxanone).

Although in general, surgical filaments made from high inherentviscosity poly(p-dioxanone) may be manufactured using conventionalmanufacturing process for bioabsorbable monofilaments, it is currentlypreferred that the filament be manufactured according to the followingguidelines.

The melt viscosity of the polymers of the present invention is importantin determining the extrusion conditions which should be used. The meltviscosity of these polymers depends on the temperature and shear rate.Generally, these polymers may be extruded at a temperature in the rangeof from about 110° C. to about 190° C., preferably in the range of fromabout 135° C. to about 165° C. and most preferably in the range of fromabout 140° C. to about 165° C. Although melt viscosities can be reducedat higher temperatures, degradation occurs at higher temperaturelimiting in practical terms the temperatures that can be used. A singleor multiple screw extruder can be used; additionally a melt pump can beemployed to increase the precision of the melt throughput, therebydecreasing the variability of the fiber diameter.

The extrudate can be taken up after a controlled-temperature-air-quenchor after being taken up though a liquid media quench bath. The extrudatemay be extruded directly into the liquid bath or an air gap may beprovided between the face of the extruder and the surface of the liquidbath. Currently, it is preferred to have an air gap of in the range offrom about 0.25 to about 1.25 inches. The extrudate, for instance, canbe taken up through a water quench bath. Currently it is preferred forthe bath temperatures to be in the range of from about 20° C. to about35° C. The rate of the extrusion as well as the quench temperature canhave an effect on the properties of the extrudate, especially itsmorphology, and thus ultimately its drawability and the properties ofthe surgical filament so produced.

The extruded filaments can be allowed to partially crystallize. This canbe accomplished by allowing the extrudate to stand at room temperaturefor a length of time prior to drawing, or by annealing the extrudate atelevated temperature, in a batch process or in-line process. The amountof time necessary to partially crystallize the extrudate is a functionof the treatment temperature. At room temperature, several hours mightbe required to partially crystallize the extrudate; in general 24 hourshas been found to be sufficient. At elevated temperatures, less time isneeded to crystallize the extrudate. The crystallinity of the extrudatecan also be increased in an in-line process prior to drawing by passingthe fibers over heated godets or through an in-line annealing oven as iscommon in the practice of fiber production.

The extrudate is subsequently drawn in a one or multistage drawingprocess in order to achieve molecular orientation and improve tensileproperties. The overall draw ratio can be as high as about 20×, but ingeneral the overall draw ratios should be in the range of from about 4×to 7.5× and preferred are overall draw ratios between 4× and 5.5×.

Although the filament may be drawn using a number of methods, thefollowing method is currently preferred. The extrudate is passed overseveral unheated godets and partially drawn. The partially drawnfilament is then passed through an in-line oven and over an additionalgodet to complete the drawing process. The temperature of the oven canvary depending on the characteristics of the extrudate, the length ofthe oven, and the linear speed of the extrudate. Currently it ispreferred that the oven be maintained at temperatures in the range offrom about 190° C. to about 400° C. The godets can be used to heat theextrudate, as well as, an oven. The draw ratio in this first stage ofdrawing can vary. Generally, the first stage draw ratios will be in therange of from about 3× to about 20×, preferred are first stage drawratios in the range of from 3× to 6× and most preferred is a first stagedraw ratio of about 4× to about 5×.

The partially drawn fibers can then be drawn in a second stage drawoperation. Draw temperatures in this second stage are generally higherthan those employed for the first stage. The second stage draw may havea draw ratio of in the range of from about 0.75× to about 3× preferablythe second draw ratio will be in the ratio of from about 1.01× to about1.5× wherein the overall draw ratio of the first and second stage drawdo not exceed 20×. As stated above it is currently preferred that theoverall draw ratio of all the stages of the drawing process should be inthe range of from about 4× to 7.5×. The resulting oriented filamentsdevelop good straight and knot tensile strengths from a two-stagedrawing process.

The speed of the godets in the drawing process will vary, but willgenerally be in the range of from about 10 feet per minute to about 200feet per minute. For example if three godets are used in a two stagedraw, the first godet should be in the range of from about 20 to about30 feet per minute, the second godet should be in the range of fromabout 80 to about 120 feet per minute and the third godet should be inthe range of from about 110 to about 145 feet per minute.

The resultant fiber can be taken up on a spool or can be relaxedslightly to give better handling characteristics. This is easilyaccomplished by allowing the fiber to pass over a set of godet rolls inwhich the linear speed of the second roll is slower than that of thefirst. This relaxation process is generally carried out at elevatedtemperature, either by heating the godet rolls or by allowing the fiberto pass through an in-line oven between the rolls.

Dimensional stability of the oriented filaments may be enhanced bysubjecting the filaments to an annealing treatment. This treatment canconsists of heating the drawn filaments to a temperature of from about40° C. to about 100° C., most preferably from about 60° C. to 90° C.while restraining the filaments to control shrinkage. Annealing canconveniently be done in an in-line process or using a rack process. In arack annealing process the filaments may be initially under tension orallowed to shrink up to about 20% prior to being restrained. Thefilaments are held at the annealing temperature for a few minutes to afew days or longer depending on the temperature and filamentcharacteristics. In general, annealing for up to about 24 hours issatisfactory for the polymers of the invention. Optimum annealing timeand temperature for maximum fiber in vivo strength retention anddimensional stability can be readily determined by simpleexperimentation for each fiber. Other spinning conditions than thoseshown here can also be employed without limiting the scope of thisinvention. Following annealing these filaments are commonly sterilizedand singly or doubly armed with needles.

The poly(p-dioxanone) sutures produced from the polymer above shouldhave an inherent viscosity of in the range of from 2.30 dL/g to about3.5 dL/g and preferably in the range of from about 2.4 dL/g to about 3.5dL/g. These sutures should have a straight tensile strength of from inthe range of from about 80,000 psi to about 400,000 psi and preferablyin the range of from 95,000 psi to about 400,000 psi. The knot strengthof sutures made from these polymers should be at least about 45,000 psiand preferably in the range of from about 45,000 psi to about 100,000psi.

The HIV poly(p-dioxanone) polymers of the present invention also can bemolded or formed using many conventional molding techniques.Conventionally, poly(p-dioxanone) is injection molded by melting thepolymer and injecting it at a volumetric flow rate of about 0.39 toabout 0.47 cubic inches per second (which corresponds to an injectionspeed of about 1 to 1.2 inches per second when using an Engel Moldingmachine with a 0.71 inch (18 mm) diameter screw with a nozzle diameterof 0.125 inches) using the minimum hydraulic pressure necessary to fillthe molds. Another method for injection molding poly(p-dioxanone) isdescribed in U.S. Pat. No. 4,490,326, which issued Dec. 25, 1984 toBeroff et al. (which is hereby incorporated by reference). Beroff foundthat by maintaining the mold temperature under 35° C. that significantimprovements in in vivo performance of ligating clips could be achieved.However, we have discovered that the injection molding HIVpoly(p-dioxanone) can be substantially improved by increasing thevolumetric flow rate of the polymer while maintaining the moldtemperatures above 35° C. Currently, it is preferred that the moldtemperatures used in injection molding HIV poly(p-dioxanone) he greaterthan 35° C., preferably in the range of from 36° C. to about 45° C. andmost preferably in the range of from about 36° C. to about 40° C.Additionally, it has been discovered that by increasing the volumetricflow rate from the conventionally used 0.47 cubic inches per second toat least 0.71 cubic inches per second (which corresponds to a injectionrate of at least 1.8 inches per second when using an Engel Moldingmachine with a 0.71 inch (18 mm) diameter screw with a nozzle diameterof 0.125 inches) improves the properties of parts which are molded.Preferably the volumetric flow rate will be in the range of from about0.71 cubic inches per second to about 2.37 cubic inches per second(which corresponds to an injection speed of from in the range of about1.8 inches per second to about 6 inches per second when using an EngelMolding machine with a 0.71 inch (18 mm) diameter screw with a nozzlediameter of 0.125 inches) and most preferably the volumetric flow ratewill be in the range of from about 0.79 cubic inches per second to about1.58 cubic inches per second (which corresponds to an injection speed inthe range of from about 2 inches per second to about 4 inches per secondwhen using an Engel Molding machine with a 0.71 inch (18 mm) diameterscrew with a nozzle diameter of 0.125 inches). Preferably the apparentwall shear rates at the nozzle of the injection molding machine will bein the range of from about 3,700 reciprocal seconds to 12,300 reciprocalseconds and most preferably in the range of from about 4,100 reciprocalseconds to about 8,200 reciprocal seconds.

Referring to the schematic flow sheet FIG. 6 the first step of themethod is to heat the polymer to a temperature above the meltingtemperature of the polymer (Box 1). A suitable temperature range formelting poly(p-dioxanone) is in the range of from about 105° C. to about140° C., preferably in the range of from about 110° C. to about 115° C.The specific apparatus used to melt poly(p-dioxanone) is not critical tothe invention, as long as, it provides adequate temperature control. Onesuitable injection molding apparatus consists of a hydraulic ram and areciprocating screw inside a heated barrel. The barrel temperature ofthis apparatus may be maintained at a temperature close to the meltingtemperature of the polymer allowing the combination of heat from thebarrel and the shearing action of the screws to provide sufficient heatto melt the polymer to be injected through a suitable nozzle. into amold. Other techniques and apparatuses for melting polymers andmaintaining polymers within a desired temperature range may also beused, including but not limited to, plunger-type molding apparatuses,injection molding apparatuses with separate accumulator devices and thelike.

The molds used may be single cavity or multi-cavity molds. However,unlike the method of molding poly(p-dioxanone) described by Beroff etal., with HIV poly(p-dioxanone) it is preferred that the molds bemaintained at a temperature above 35° C. and preferably in the range offrom 36° C. to about 45° C. and most preferably in the range of fromabout 36° C. to about 40° C. (Box 2).

The polymer should be injected into the mold under pressure, preferablyin the range of from about 500 to about 1650 pounds per square inch (Box3). The injection pressure should be 30 psi above the minimum hydraulicpressure required to fill all the cavities in the mold and preferablywill be in the range of from about 50 to about 75 psi above the minimumhydraulic pressure required to fill all the cavities in the mold. Afterthe polymer is injected into the mold, pressure should be maintained onthe polymer in the mold to pack and maintain its desired shape (Box 4).Currently, it is preferred that this hold pressure is in the range offrom about 50 percent to about 85 percent of the initial pressure (inthe range of from about 250 to about 1400 psi) maintained during theholding phase of molding cycle. Preferably the pressure maintainedduring the holding cycle will be in the range of from about 65 percentto about 85 percent of the initial pressure and most preferably about 75percent of the initial pressure. The pressure should be maintained onthe polymer for at least 3 seconds and preferably for at least 4seconds. The molded device may be removed from the mold after a suitablecooling time (Box 5) of 75 to 120 seconds. Preferably the cooling timeshould be of a duration of 90 to 105 seconds. This molding process isparticularly well suited to molding small surgical devices such asstaples and clips where the mass of the molded device is less than 5grams and preferably less than 2 grams.

Molded devices of poly(p-dioxanone) may be annealed and sterilizedsubsequent to molding. Annealing these molded devices is often done tostabilize or improve the properties of the device. Suitable techniquesfor annealing molded devices containing poly(p-dioxanone) are describedin U.S. Pat. No. 4,620,541 issued on Nov. 4, 1986 to Gertzman et al.(which is hereby incorporated by reference). Sterilization may beaccomplished by any suitable means known to those skilled in the art.

The following non-limiting Examples are provided to further illustratethe present invention.

EXAMPLE I

This example describes a method for testing p-dioxanone monomer for itssuitability for making high molecular weight poly(p-dioxanone).

To a clean, dry glass ampoule having a neck approximately 30 cm inlength, 14 mm in internal diameter, terminating first in a swollen necksection to accommodate solids overflow during loading and finally in aspherical bulb of approximately 25 mL of internal volume, is charged aclean, dry magnetic spin bar, 20.0 grams of p-dioxanone monomer to betested, and 0.039 mL of a 0.0331M stannous octoate in toluene solution.The transfer is generally conducted in a dry nitrogen glove box so asnot to expose the ingredients to atmospheric moisture and care is takennot to leave deposits on the neck of the ampoule.

The ampoule is connected to a vacuum manifold and purged with drynitrogen to remove the small amount of toluene present. The ampoule isevacuated to a pressure of 100 microns for a period of 40 to 45 minutes.After this time, the pressure is adjusted with dry nitrogen tocorrespond to 5 inches of Hg, and the ampoule is hermetically sealed bycollapsing shut the upper region of the neck by flaming with a suitabletorch. The charged ampoule is immersed in a silicon oil bath preheatedto 120° C., and positioned above a suitable magnetic stirrer. Mixing byvirtue of the spin bar/stirrer system is begun almost immediately; aspolymer is formed the molten mass becomes too viscous for the magneticspin bar to be effective and the stirrer is shut off. After 20 hours ofheating at 120° C., the ampoule is carefully removed from the oil bath,wiped with a clean cloth to remove silicon oil from the surface, and setaside to cool to room temperature.

The reaction mass, a combination of formed polymer and residualunreacted monomer, is isolated by immersing the ampoule in liquidnitrogen followed by breaking the glass away, typically with a hammer.The reaction mass is sampled by using a twist drill and bit, drilling ata slow rate of approximately 1 revolution per second into the center ofthe mass approximately 1/2 inch down. The inherent viscosity of piecesremoved from the center section of the "test egg" is determined inhexafluoroisopropanol.

EXAMPLE II

This example describes a process for producing poly(p-dioxanone) with ahigh inherent viscosity.

Poly(p-dioxanone) polymer can be produced either in a one-steppolymerization in a reactor capable of handling high viscosity polymersor in a two-step polymerization whereby a low molecular weightpre-polymer is transferred to curing trays for a second stage solidstate polymerization to achieve maximum conversion.

Formula

The example described herein is formulated for the two stepprepolymer/solid state polymerization. For this example 182.2 moles(18.584 kg) of p-dioxanone monomer of average test inherent viscosity3.31 dL/g were used to produce a high IV poly(p-dioxanone) polymer oftarget inherent viscosity of 2.61 dL/g and a melt index of 0.035 g/10min. as determine with standard ASTM equipment at 150° C. with an addedweight of 6,600 g using a modified ASTM cylindrical die with a 0.0260inch diameter. The quantity of molecular weight control agent added tothe polymerization is the difference between the estimated number ofmoles of MWCA based on overall moles of monomer per mole of MWCA and thenumber of moles of MWCA contained in the monomer as impurities. Based onEquation (3) above, an overall ratio of 849 moles of monomer per mole ofcombined molecular weight control agents was required to provide apolymer of desired properties. The combined impurities of thep-dioxanone monomer with a test polymerization of 3.31 dL/g wasestimated to account for 0.0001208 moles of MWCA as impurities (8279moles of impurity type molecular weight control agent per mole ofmonomer). The amount of actual molecular weight control agent added tothe reaction was determined per Equation 2, to be 0.0010571 moles ofmolecular weight control agent per mole of monomer (or 946 moles ofmonomer per mole of molecular weight control agent). Stannous octoatecatalyst in the range of from about 10,000 to about 100,000 moles ofmonomer per mole of catalyst can be used for solid state polymerization.The example described herein used a 0.331 molar stannous octoatecatalyst solution at a ratio of 25,000 moles of monomer per mole ofstannous octoate. The optimum catalyst level is a function of dye leveland type, as well as, polymerization temperature. At too low a catalystratio the polymerization is extremely slow and will not result in thecomplete conversion of monomer to polymer. At too high a catalyst ratiothe polymer will degrade when reheated during melt processing.

Procedure

Approximately half of the 182.2 moles of p-dioxanone monomer (testIV=3.31 dL/g) was charged to a preheated (65° C.) fifteen gallonstainless steel reactor while being purged with nitrogen. Thepolymerization can take place with or without reactor preheating. D&Cviolet #2 dye (18.6 g or 0.1 wt % of the charged monomer) was mixed witha portion of the monomer and added to the reactor. The remaining portionof p-dioxanone monomer was then added to the reactor. The amount ofdodecanol to be added was calculated using Equation (8). The calculatedquantity of dodecanol (35.9 g), the intentionally added molecular weightcontrol agent, was added to the reactor also while under a nitrogenpurge. Stannous octoate catalyst (22.04 mL of a 0.331 molar solution intoluene) was then added to the reactor, again under a nitrogen purge toprevent the addition of moisture. The reactor was sealed. The pressurein the reactor was reduced to 1000 microns or less, maintained there fortwenty minutes and then nitrogen introduced to develop an overpressureof 0-2 psig. This evacuation/nitrogen purge step was repeated a total ofthree times. The oil circulating through the jacket was increased to110° C. to initiate polymerization. When the batch temperature reached90° C. (in about 15 minutes), the oil temperature was reduced to 95° C.Polymer viscosity, as determined with a Brookfield Model DV-IIViscometer using a no. 2 spindle, was monitored by removing a portion ofthe molten mass through a valve located at the bottom of the reactor.The entire contents of the reactor were discharged under nitrogen intocuring trays when a viscosity between 100 and 500 cp had been reached. Acuring tray consists of a sealable container made of metal, plastic orother suitable material which does not deform or degrade at 120° C. anddoes not react with the polymerization mass to render it unsuitable. Thetrays used herein are 9 inch diameter formed-aluminum trays. A teflon orteflon coated metal lid is used to provide the closed storage containerduring curing.

The curing trays were sealed under nitrogen blanket and placed into anitrogen-purged oven set at 80° C. We have found that reactiontemperatures between about 65 and 95° C. are suitable for a solid-statepost curing, but that temperatures between 70° and 90° C. are preferred,and most preferred is about 80° C. The reaction mass can be heated forbetween about two and seven days depending on the curing temperature. Wehave found that at 80° C., a curing time between three and five days issuitable. The polymer of this example was cured at 80° C. for 4 days.

The cured polymer was removed from the oven, allowed to cool to roomtemperature and then removed from the curing trays. The polymer wassampled to determine properties, weighed, placed in plastic bags andthen transferred to freezer storage until required for the next step,size reduction. The cold and brittle polymer was removed from freezerstorage and immediately placed in a Cumberland grinder for sizereduction. A 3/16 inch grinder screen was used to provide the desiredparticle size. The ground polymer was then sieved in conventional sizeseparation equipment to remove fines (less than 18 mesh) and oversizedpieces of polymer (greater than 1/4 inch). The ground and sieved polymerwas then transferred to a vacuum tumble dryer to reduce the small amountof unreacted monomer. The drying cycle consisted of a 10 hour vacuumphase without heat to remove moisture picked during size reduction, a 32hours heat and vacuum phase to remove unreacted monomer, followed by acool-down phase to allow the polymer to approach room temperature whilestill under vacuum. The dryer achieved a vacuum corresponding to apressure of 200 microns or less at the end of the devolatilizationcycle. The dried polymer was then transferred to vacuum storage vesselsand placed under vacuum to await disposition. Test samples were removedduring dryer discharge.

The resultant polymer had an inherent viscosity of 2.53 and a melt indexof 0.043 g/10 min. The melting point, as determined by DSC (first heat)using a scan rate of 20° C./min, was determined to be 119° C.

EXAMPLE III

Suture knot clips were molded from several different inherentviscosities of poly(p-dioxanone) produced following the processdescribed in Example II. The data from in vivo testing of these knotclips demonstrates that a significant improvement in knot clip in vivosurvival can be achieved by increasing the molecular weight ofpoly(p-dioxanone).

Three grades of poly(p-dioxanone) with inherent viscosities respectivelyof from 1.91 dL/g, 2.07 dL/g and 2.35 dL/g (all determined at 25° C. ata concentration of 0.1 g/dL in hexafluoroisopropanol) were evaluated inmolded suture knot clips possessing both a hinge and a latch designsimilar to the suture knot clip design described in EPA-519,703 (herebyincorporated by reference). The three grades of poly(p-dioxanone) weremelted at a temperature of from 104°-112° C. The melted polymer wasinjected molded using a 30 ton Engel OM361-002 molding machine with a0.71 inch diameter (18 mm) screw and a nozzle diameter of 0.125 inchesfitted with a four cavity mold. The melted polymer was injected with aboost pressure of from 625-1125 psi. The molds were maintained at atemperature of 39°-53° C. The molded parts were ejected after 75 to 105seconds.

The suture knot clips were then locked on a 2/0 coated Vicryl™ sutureand implanted in rats. Fourteen days later the knot clips were carefullyremoved from the rats and evaluated. The clips were evaluated todetermine if the latches remained closed and the hinges remained intact.A clip was considered to have survived in vivo if the latch was stillcompletely closed over the suture strand and the hinge was not brokenwhen the clips were removed from the rats. The data from these tests arepresented graphically in FIG. 5.

The data in FIG. 5 conclusively demonstrates that with an inherentviscosity of 1.91 dL/g only 16 of 40 sample groups tested have a 90%survival rate for suture knot clips. Increasing the inherent viscosityto 2.07 dL/g results in 25 of 36 sample groups tested having a 90%survival rate for the suture knot clips. However, increasing theinherent viscosity to 2.35 dL/g results in all 32 sample groups testedhaving a 90% survival rate and 24 out of 32 groups having a 100%survival rate.

Thus, by increasing the inherent viscosity of poly(p-dioxanone) (from1.91 dL/g to 2.07 dL/g) used in molding suture clips, the in vivosurvival of the clips can be significantly increased.

EXAMPLE IV

This example provides a comparison of the properties ofpoly(p-dioxanone) sutures having an initial inherent viscosity of 1.71dL/g and 2.28 dL/g. This sutures were prepared under the followingconditions:

                  TABLE I    ______________________________________    POLY(p-DIOXANONE) SUTURES    ______________________________________    Initial IV of    1.72 dL/g                              2.64 dL/g    Polymer    IV of Polymer   <1.72 dL/g                              2.28 dL/g    after Extrusion    Temperatures °C.    Barrel Zones    114/117/119                              145/155/148    1/2/Flange    Pump            119       155    Block           119       158    Die             122       154    Quench Conditions    Air Gap, Inch   1/2       1/4    Water Temp, °C.                    22        25    Roll Speed, FPM 9.5       23    Air Quench      115       AMB    Cabinet Temp °C.    Drawing Conditions    Speed, FPM      9.5       24    Godet 1 Speed,  10        25    FPM    Godet 2 Speed,  52        109    FPM    Oven Temp, °C.                    220       325    Godet 3 Speed,  60        130    FPM    Draw Ratios    First Stage     5.2       4.4    Second Stage    1.15      1.19    Total Draw      6.0       5.2    Ratio    ______________________________________

The characteristic properties of the sutures of the invention arereadily determined by conventional test procedures. The tensileproperties (i.e., straight and knot tensile strengths and elongation)displayed herein were determined with an INSTRON tensile tester. Thesettings used to determine the straight tensile, knot tensile and breakelongation were the following:

                  TABLE II    ______________________________________            GAUGE                CROSSHEAD            LENGTH  CHART SPEED  SPEED            (cm)    (cm)         (cm/min)    ______________________________________    STRAIGHT  12.7      30.5         30.5    TENSILE    KNOT      12.7      30.5         30.5    TENSILE    BREAK     12.7      30.5         30.5    ELONGATION    ______________________________________

The straight tensile strength is calculated by dividing the force tobreak by the initial cross-sectional area of the suture. The elongationat break is read directly from the stress-strain curve of the sample.

The knot tensile strength of a suture is determined in separate tests.The surgeon's knot is a square knot in which the free end is firstpassed twice, instead of once, though the loop, and the ends drawn tautso that a single knot is superimposed upon a compound knot. The firstknot is started with the left end over the right end and sufficienttension is exerted to tie the knot securely.

The specimen is placed in the INSTRON tensile tester with the knotapproximately midway between the clamps. The knot tensile strength iscalculated by dividing the force required to break by the initialcross-sectional area of the fiber. The tensile strength values arereported as KPSI (which means PSI×10³).

                  TABLE III    ______________________________________    PHYSICAL    PROPERTIES OF    Poly(p-     Poly(p-dioxanone)                               Poly(p-dioxanone)    dioxanone)  IV 1.72 Initial                               IV 2.64 Initial    Sutures     Polymer Viscosity                               Polymer Viscosity    ______________________________________    Diameter, MIL                16.8           15.8    Strengths, KPSI    Straight, KPSI                73.9           97.2    Knot, KPSI  40.2           48.5    Elongation, %                26.3           32.2    Toughness, TE.sup.1/2                379            551    KPSI    ______________________________________

The data in Table II demonstrates the very significant changes instraight strength, knot strength and elongation which occur where themolecular weight of poly(p-dioxanone) is increased in sutures. Thestraight strength of the suture increased by 31.5 percent and the knotstrength and elongation of the suture increased by greater than 20percent. The toughness of the fiber also increased by greater than 45percent (tensile strength multiplied by the square root of elongation tobreak).

It should be recognized that the extraordinary improvement in theproperties of the high inherent viscosity filament were obtained usingan unoptimized extrusion and drawing process. Therefore, it is expectedthat by routine experimentation the temperature for extrusion and thedraw ratios for orienting the filament can be optimized to furtherimprove the properties of filaments made from high inherent viscositypoly(p-dioxanone).

EXAMPLE V

This Example describes the mechanical testing procedures for injectionmolded poly(p-dioxanone) tensile bar test articles. The data from themechanical tests is presented in FIGS. 1-4.

Three lots of poly(p-dioxanone) polymer, having different inherentviscosities, were molded into tensile bar test articles (dogbones) formechanical testing. A poly(p-dioxanone) resin exhibiting an inherentviscosity of 1.86 dL/g was molded into tensile bar test articles usingan Arburg Model 170-CMD/E injection molder with a size 15 mmplasticizing cylinder and equipped with a general purpose screw; thehopper was outfitted with a nitrogen purge to keep the resin dry. Thefeed, transition, and compression zone temperatures were 121°, 143°, and143° C., respectively, while the nozzle and mold temperatures were 129°and 40° C. A maximum injection speed of 12 cc/sec was used. Theinjection pressure experienced was 2495 bars. For each cycle, a totalhold-time-under-pressure of 11 seconds was used and the mold was heldclosed for 40 seconds; a typical cycle time was 58 seconds.

Two poly(p-dioxanone) resins exhibiting inherent viscosities of 2.13 and2.43 dL/g respectively were molded into tensile bar test articles(dogbones) using an Arburg Model 170-90-200 injection molder with a size18 mm plasticizing cylinder and equipped with a general purpose screw;the hopper was outfitted with a nitrogen purge to keep the resin dry.Molding conditions including specific machine settings are shown inTable IV below:

                  TABLE IV    ______________________________________    Inherent Viscosity of the Resin,                               2.13     2.43    dL/g:    Feed Zone Temperature, °C.:                               108      114    Transition Zone Temperature, °C.:                               109      116    Compression Zone Temperature, °C.:                               109      116    Nozzle Temperature, °C.:                               110      117    Melt Temperature, °C.:                               107-108  114-115    Mold Temperature, °C.:                               39-40    39-40    Hydraulic Pressure, psi                      Boost:   1600     2000                      Hold:    1200     1250    Mold Closing:     V1       3        3                      P1       10       10                      V2       1        1    Injection Speeds: V3       90       95                      V4       90       95    Injection Pressures:                      P2       70       90                      P3       50       55                      P4       00       00    Screw Speed:      V5       45       45    Screw RPM:                 200      200    Back Pressure:    P5       25       25    Mold Open:        V6       3        3                      V7       2        2    Knock Out Forward:                      V10      2        2                      P8       2        2    Knock Out Return: V11      1        1                      P9       1        1    Cycle Time, sec:  t1       72.6     73.5    Injection Time, sec:                      t2       3.0      3.0                      t3       5.0      5.0                      t4       3.0      3.0    Cooling Time, sec:                      t5       50.0     50.0    Die Open Time, sec:                      t6       0.5      0.5    Mold Protect Time, sec                      t7       2.0      2.0    Delayed Injection Time, sec:                      t8       2.0      2.0    ______________________________________

In general, high molecular weight poly(p-dioxanone) polymers generatehigher melt viscosities than corresponding moderate molecular weightpolymers, leading to higher processing pressures. It is common to offsethigh melt viscosities by employing processing temperatures but this hasa practical limit due to the increased degradation that occurs at highertemperatures. Some injection molding machines are incapable ofgenerating the pressures required to mold higher molecularpoly(p-dioxanone) resins. Thus, to fully benefit from the increasedproperties that the polymers of the subject invention can provide,machines capable of generating the pressures required to process saidresins must be employed.

The mechanical properties of injection molded dogbone test articles weredetermined using a Model 4201 Instron Tensile Testing machine equippedwith an Instron 10 mm gauge length, self-identifying, strain gaugeextensometer having a maximum strain specification of 50 percent. Themachine was operated with a crosshead speed of 0.50 inches per minute.The molded dogbone test articles were 3.26 inches in overall length and0.040 inches thick. The two tab sections of the dogbones were each 0.375inches wide by 1.00 inches long; the uniform central gauge section was0.600 long by 0.125 inches wide (and 0.040 inches thick). The transitionsection connecting the two tab sections to the central gauge section wasdefined by a radii of 0.500 inches tangent to the gauge section.

EXAMPLE VI

The data in Example III conclusively demonstrates that significantlyimproved in vivo survival of suture knot clips can be obtained byincreasing the molecular weight of poly(p-dioxanone). In this example,it will be demonstrated that certain changes in the injection molding ofsuture clips lead to further significant improvements in the in vivosurvival and tensile properties.

Poly(dioxanone) polymers with inherent viscosity respectively of from1.87 to 1.92 dL/g (determined at 25° C. at a concentration of 0.1 g/dLin hexafluoroisopropanol) were used to make suture knot clips possessingboth a hinge and a latch. The polymers were melted with melttemperatures between 104° to 107° C. and the melted polymers were theninjection molded using the conditions listed in Processing Condition Iin Table V using a 30 ton Engel molding machine with a 0.71 inchdiameter (18 mm) screw and a nozzle diameter of 0.125 inches fitted witha 4 cavity mold. The injection pressure was the minimum hydraulicpressure required to fill the mold. The injection speed of 1.0 to 1.2inches per second corresponds to a volumetric flow rate of 0.39 to 0.47cubic inches per second with an apparent wall shear rate of 2100 to 2500reciprocal seconds at the nozzle.

                  TABLE V    ______________________________________               Processing  Processing Processing    Process Parameter               Condition I Condition II                                      Condition III    ______________________________________    Mold Temperature               39-45       38-44      36-40    (°C.)    Hold Time (sec)               4           4          4    Cooling Time (sec)               60-70       100        100    Injection Pressure               Minimum     Minimum    Minimum    (psi)      Hydraulic   Hydraulic  Hydraulic               Pressure required                           Pressure to fill                                      Pressure to fill               to fill the mold                           the mold + 50                                      the mold + 50                           psi        psi    Hold pressure               450-550     75% of     75% of               psi         Injection  Injection                           Pressure   Pressure    Injection Speed               1.0-1.2     1.2        2.4    (in/sec)    ______________________________________

The suture knot clips were then locked or clamped on a 3/0 coatedVicryl™ suture and implanted in rats. Ten days later the knot clips werecarefully removed from the rats and evaluated. The clips were evaluatedto determine if the latches remained closed and the hinges remainedintact. A clip was considered to have survived in vivo, if the latch wascompletely closed over the suture strand and the hinge was not brokenwhen the clips were removed from the rats. Ten. random clips were testedfor 10 days. For clips made from polymers with inherent viscosityrespectively of from 1.87 to 1.92 dL/g, all clips successfully survivedfor 10 days.

A poly(dioxanone) polymer with inherent viscosity of 2.18 dL/g(determined at 25° C. at a concentration of 0.1 g/dL inhexafluoroisopropanol) was used to make suture knot clips possessingboth a hinge and a latch using injection molding technique. The moldingmachine used was a 30 ton Engel molding machine with a 0.71 inchdiameter (18 mm) screw and a nozzle diameter of 0.125 inches fitted witha 8 cavity mold with 4 inner and 4 outer cavities. The conditions usedto mold the knot clips are described as Process Condition II in Table V.Although the inherent viscosity of polymer was higher than the inherentviscosity of the polymer used to make clips following Process Conditions1, the injection molding conditions were similar. The polymer was meltedusing barrel set point settings of 106° C. in the feed zone andtemperatures settings in the other 3 zones of the barrel and in thenozzle were the same for any particular run and varied between 106° to108° C. The mold temperature varied from 38 to 44° C. The injectionpressure was 50 psi above the minimum hydraulic pressure required tofill the mold. The injection speed of 1.2 inches per second correspondsto a volumetric flow rate of 0.47 cubic inches per second with anapparent wall shear rate of 2500 reciprocal seconds at the nozzle. Theother molding conditions used are listed in Processing Condition II inTable V.

The suture knot clips were then locked or clamped on a 2/0 coatedVicryl™ suture and implanted in rats. The 2/0 coated Vicryl™ has alarger diameter than the 3/0 suture which the knot clips from ProcessCondition I were previously tested on. Fourteen and sixteen days later,the knot clips were carefully removed from the rats and evaluated. Theclips were evaluated to determine if the latches remained closed and thehinges remained intact. A clip was considered to have survived in vivoif the latch was completely closed over the suture strand and the hingewas not broken when the clips were removed from the rats. Also, theclips were visually inspected to determine the relative level ofcracking that occurred in the explanted clips. Forty random clips (5 percavity) were tested for fourteen and sixteen days in vivo survival.

The data in Table VI shows the tensile properties of inner and outercavities and the in vivo survival after sixteen days. Inner and Outer inTable VI refers to an average value of tensile properties obtained fromfour inner and four outer cavities, respectively; ten clips were testedper cavity. Hinge refers to maximum tensile load (in pounds)demonstrated by the suture knot clip during tensile testing usingInstron Tensile Testing Machine with attachments to grip the two beamsof the suture knot clip. Elong. refers to the elongation values (ininches) at break in the hinge area of the suture knot clip duringtensile testing. Energy refers to energy at break (in pound-inch) duringtensile testing and is measured as the area under load-displacementcurve obtained during tensile testing. It is evident that suture knotclips from outer cavities have lower properties than suture knot clipsfrom inner cavities. At fourteen days three groups of suture knot clipshad a 100 percent survival and one group had less than 100 percentsurvival. At sixteen days two groups had 100 percent survival and twogroups had less than 100 percent survival. All the in vivo failures wereobserved with clips molded in the outer cavities. The level of crackingin general was more pronounced at sixteen days as compared to fourteendays. The crack evaluations demonstrated that the clips from the outercavities have more cracking compared to clips from inner cavities fromthe same processing conditions. Although there were still some fourteenand sixteen day in vivo failures on knot clips from Process ConditionII, it is still evident that the use of higher inherent viscositypoly(p-dioxanone) in Process Condition II allows the clips to survivefor longer in vivo periods under the greater strain of a larger diametersuture as compared to the lower inherent viscosity polymer used inProcess Condition I.

                                      TABLE VI    __________________________________________________________________________    Melt Temp/    Mold Temp/           Inner                Outer                    Inner                         Outer                             Inner                                  Outer                                      16 Day    Injection           Hinge                Hinge                    Elong.                         Elong.                             Energy                                  Energy                                      In Vivo    Pressure           (lb) (lb)                    (in) (in)                             (lb-in)                                  (lb-in)                                      Survival    __________________________________________________________________________    106° C./44° C.           11.6 10.3                    0.069                         0.051                             0.612                                  0.397                                       95%    1096 psi    106° C./38° C.           12.3 9.7 0.084                         0..056                             0.750                                  0.409                                      100%    1149 psi    108° C./42° C.           11.2 9.8 0.073                         0.056                             0.598                                  0.419                                      100%    1051 psi    108° C./38° C.           12.3 10.0                    0.084                         0.058                             0.761                                  0.424                                       95%    1072 psi    __________________________________________________________________________

Poly(p-dioxanone) polymer with inherent viscosity of 2.18 dL/g(determined at 25° C. at a concentration of 0.1 g/dL inhexafluoroisopropanol) was used to make suture knot clips possessingboth a hinge and a latch using injection molding technique and using a30 ton Engel molding machine with a 0.71 inch diameter (18 mm) screw anda nozzle diameter of 0.125 fitted with a 8 cavity mold with 4 inner and4 outer cavities. The polymer was melted using barrel set point settingsof 106° C. in the feed zone and temperatures settings in the other 3zones of the barrel and in the nozzle are same for any particular runand was varied between 110° to 114° C. The mold temperature varied from36° to 40° C. The injection speed of 2.4 inches per second correspondsto a volumetric flow rate of 0.94 cubic inches per second and anapparent wall shear rate of 4900 reciprocal seconds at the nozzle. Theinjection pressure was 50 psi above the minimum hydraulic pressurerequired to fill the mold. The other conditions are specified inProcessing Condition III in Table V.

The suture knot clips were then locked or clamped on a 2/0 coatedVicryl™ suture and implanted in rats. Sixteen days later the knot clipswere carefully removed from the rats and evaluated. The clips wereevaluated to determine if the latches remained closed and the hingesremained intact. A clip was considered to have survived in vivo if thelatch was completely closed over the suture strand and the hinge was notbroken when the clips were removed from the rats. Also the clips werevisually inspected to determine the relative level of cracking thatoccurred in the explanted clips. Forty random clips (5 per cavity) weretested for 16 days in vivo survival.

The data in Table VII shows the tensile properties of inner and outercavities and the in vivo survival after 16 days. It is clearly evidentthat suture knot clips from outer cavities have lower elongation atbreak and lower energy to break than suture knot clips from innercavities and the hinge strengths are almost identical between inner andouter cavities. However, the tensile properties in Table VII weresignificantly higher than shown in Table VI. There were no in vivofailures in clips from either inner or outer cavities. The crackevaluations revealed that there was no significant difference incracking between clips from outer and inner cavities from the sameprocessing conditions arising out of higher injection speeds and lowermold temperatures. The in vivo results in Table VII showed significantimprovements compared to the results reported in Table VI.

                                      TABLE VII    __________________________________________________________________________    Melt Temp/    Mold Temp/           Inner                Outer                    Inner                         Outer                             Inner                                  Outer                                      16 Day    Injection           Hinge                Hinge                    Elong.                         Elong.                             Energy                                  Energy                                      In Vivo    Pressure           (lb) (lb)                    (in) (in)                             (lb-in)                                  (lb-in)                                      Survival    __________________________________________________________________________    110° C./40°           12.3 12.1                    0.095                         0.086                             0.886                                  0.786                                      100%    C./1106 psi    114° C./40°           12.1 12.0                    0.091                         0.085                             0.822                                  0.779                                      100%    C./975 psi    114° C./36°           12.6 12.5                    0.099                         0.091                             0.947                                  0.865                                      100%    C./995 psi    110° C./36°           12.8 12.5                    0.106                         0.089                             1.018                                  0.840                                      100%    C./1051 psi    __________________________________________________________________________

It should be recognized that the significant improvement in theproperties and in vivo performance of the high inherent viscosity sutureknot clips was obtained using higher volumetric injection rates andlower mold temperature.

We claim:
 1. A method of producing a high inherent viscositypoly(p-dioxanone) polymer with a predetermined inherent viscositycomprising:a) determining the amount of water, free acid and reactiveimpurities in a lot of monomer of p-dioxanone by a test polymerizationof the monomer; then b) selecting the desired inherent viscosity whereinthe relative amount of polymerization initiator (1/R_(mwca)) added tothe polymerization of the lot of monomer is determined using thefollowing formula:

    1/R.sub.mwca =(A/IV).sup.(1/a) -1/(B*IV.sub.m.sup.b)

wherein a is in the range of from about 0.61 to about 0.71, A is in therange of from about 0.015 to about 0.058, b is in the range of fromabout 3.4 to about 7.5, and B is in the range of from about 3.7 to about76; c) adding the amount of polymerization initiator as determined instep b to obtain the desired inherent viscosity; d) polymerizing the lotof monomer in a suitable reaction vessel under suitable conditions forpolymerizing the monomer in the presence of an organo-tin catalyst withan amount of polymerization initiator in an amount sufficient aftertaking into account the presence of the reaction impurities in themonomer to provide a poly(p-dioxanone) containing polymer having aninherent viscosity of greater than 2.3 dL/g.
 2. The process of claim 1wherein the test polymerization of the monomer is performed with in therange of from about 10,000 to about 100,000 moles of monomer per mole ofan organo-tin catalyst, the polymerization is performed at from in therange of from about 60° to about 140° C. for in the range of from about2 to about 7 days.
 3. A method of producing a high inherent viscositypoly(p-dioxanone) polymer with a predetermined inherent viscositycomprising:a) determining the amount of water, free acid and reactiveimpurities in a lot of monomer containing at least 80 mole percent ofp-dioxanone the balance of the monomer being a lactone monomer selectedfrom the group consisting glycolide, lactide, ε-caprolactone andtrimethylene carbonate; by a test polymerization of the monomer; then b)selecting the desired inherent viscosity wherein the relative amount ofpolymerization initiator (1/R_(mwca)) added to the polymerization of thelot of monomer is determined using the following formula:

    1/R.sub.mwca =(A/IV).sup.(1/a) -1/(B*IV.sub.m.sup.b)

wherein a is in the range of from about 0.61 to about 0.71, A is in therange of from about 0.015 to about 0.058, b is in the range of fromabout 3.4 to about 7.5, and B is in the range of from about 3.7 to about76; c) adding the amount of polymerization initiator as determined instep b to obtain the desired inherent viscosity; d) polymerizing the lotof monomer in a suitable reaction vessel under suitable conditions forpolymerizing the monomer in the presence of an organo-tin catalyst withan amount of polymerization initiator in an amount sufficient aftertaking into account the presence of the reaction impurities in themonomer to provide a poly(p-dioxanone) containing polymer.